Uterine natural killer cells (uNK) are an innate lymphoid population that are critical determinants of pregnancy success. Despite extensive research, fundamental knowledge gaps remain regarding the origin and composition of uNK cells in the endometrium and the molecular mechanisms driving uNK differentiation. These gaps result in part from our inability to address these essential questions in a human model. We have combined cutting-edge next generation sequencing methodologies with access to human uterus transplant recipients to answer questions about uNK trafficking, function and differentiation that will advance our understanding of pregnancy and its complicatons. The central premise of this proposal is that placentation, and therefore pregnancy fate, is pre-determined in part by the differentiation of uNK cells which populate the maternal-fetal interface prior to embryo implantation. Herein, we build upon this premise and test the following hypotheses: 1) uNKs which derive from peripheral and tissue-resident progenitor populations possess distinct transcriptional signatures, and 2) the Nuclear Factor of Activated T cells (NFAT) is a key transcription factor that promotes the differentiation of immature endometrial NK cells into mature decidual NK cells. Uterus transplant recipients provide an opportunity to answer foundational questions about uNK cell biology in human beings and will yield new insights into the pathogenesis of pregnancy complications.